Ruxolitinib treatment reduces monocytic superoxide radical formation without affecting hydrogen peroxide formation or systemic oxidative nucleoside damage in myelofibrosis

References

• Hasselbalch HC. Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer? Blood. 2012;119:3219–3225.
   PubMed Web of Science ®Google Scholar
• Hasselbalch HC. A role of NF-E2 in chronic inflammation and clonal evolution in essential thrombocythemia, polycythemia vera and myelofibrosis? Leuk Res. 2014;38:263–266.
   PubMed Web of Science ®Google Scholar
• Hasselbalch HC, Bjørn ME. MPNs as inflammatory diseases: the evidence, consequences, and perspectives. Mediators Inflamm. 2015;2015:1–16.
   Web of Science ®Google Scholar
• Koschmieder S, Mughal TI, Hasselbalch HC, et al. Myeloproliferative neoplasms and inflammation: whether to target the malignant clone or the inflammatory process or both. Leukemia. 2016;30:1018–1024.
   PubMed Web of Science ®Google Scholar
• Hermouet S, Hasselbalch HC, Čokić V. Mediators of inflammation in myeloproliferative neoplasms: state of the art. Mediators Inflamm. 2015;2015:1–3.
   Web of Science ®Google Scholar
• Hermouet S, Vilaine M. The JAK2 46/1 haplotype: a marker of inappropriate myelomonocytic response to cytokine stimulation, leading to increased risk of inflammation, myeloid neoplasm, and impaired defense against infection? Haematologica. 2011;96:1575–1579.
   PubMed Web of Science ®Google Scholar
• Barbui T, Carobbio A, Finazzi G, et al. Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3. Haematologica. 2011;96:315–318.
   PubMed Web of Science ®Google Scholar
• Tefferi A, Vaidya R, Caramazza D, et al. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. JCO. 2011;29:1356–1363.
   PubMed Web of Science ®Google Scholar
• Pardanani A, Finke C, Abdelrahman RA, et al. Associations and prognostic interactions between circulating levels of hepcidin, ferritin and inflammatory cytokines in primary myelofibrosis. Am J Hematol. 2013;88:312–316.
   PubMed Web of Science ®Google Scholar
• Hasselbalch HC. The role of cytokines in the initiation and progression of myelofibrosis. Cytokine Growth Factor Rev. 2013;24:133–145.
   PubMed Web of Science ®Google Scholar
• Skov V, Larsen TS, Thomassen M, et al. Molecular profiling of peripheral blood cells from patients with polycythemia vera and related neoplasms: identification of deregulated genes of significance for inflammation and immune surveillance. Leuk Res. 2012;36:1387–1392.
   PubMed Web of Science ®Google Scholar
• Skov V, Thomassen M, Riley CH, et al. Gene expression profiling with principal component analysis depicts the biological continuum from essential thrombocythemia over polycythemia vera to myelofibrosis. Exp Hematol. 2012;40:771–780.e19.
   PubMed Web of Science ®Google Scholar
• Vener C, Novembrino C, Catena FB, et al. Oxidative stress is increased in primary and post-polycythemia vera myelofibrosis. Exp Hematol. 2010;38:1058–1065.
   PubMed Web of Science ®Google Scholar
• Hasselbalch HC, Thomassen M, Riley CH, et al. Whole blood transcriptional profiling reveals deregulation of oxidative and antioxidative defence genes in myelofibrosis and related neoplasms. Potential implications of downregulation of Nrf2 for genomic instability and disease progression. PLoS One. 2014;9:e112786.
   PubMed Web of Science ®Google Scholar
• Desterke C, Martinaud C, Ruzehaji N, et al. Inflammation as a keystone of bone marrow stroma alterations in primary myelofibrosis. Mediators Inflamm. 2015;2015:1.
   Web of Science ®Google Scholar
• Marty C, Lacout C, Droin N, et al. A role for reactive oxygen species in JAK2 V617F myeloproliferative neoplasm progression. Leukemia. 2013;27:2187–2195.
   PubMed Web of Science ®Google Scholar
• Lundberg P, Karow A, Nienhold R, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood. 2014;123:2220–2228.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Kralovics R. From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood. 2014;123:3714–3719.
   PubMed Web of Science ®Google Scholar
• Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.
   PubMed Web of Science ®Google Scholar
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.
   PubMed Web of Science ®Google Scholar
• Colotta F, Allavena P, Sica A, et al. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30:1073–1081.
   PubMed Web of Science ®Google Scholar
• Janiszewska H, Bak A, Pilarska M, et al. A risk of essential thrombocythemia in carriers of constitutional CHEK2 gene mutations. Haematologica. 2012;97:366–370.
   PubMed Web of Science ®Google Scholar
• Janiszewska H, Bąk A, Hartwig M, et al. The germline mutations of the CHEK2 gene are associated with an increased risk of polycythaemia vera. Br J Haematol. 2015;173:150–152.
   PubMed Web of Science ®Google Scholar
• Yalcin S, Marinkovic D, Mungamuri SK, et al. ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice. EMBO J. 2010;29:4118–4131.
   PubMed Web of Science ®Google Scholar
• Ahn JS, Li J, Chen E, et al. JAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL deamidation. Oncogene. 2016;35:2235–2246.
   PubMed Web of Science ®Google Scholar
• Kagoya Y, Yoshimi A, Tsuruta-Kishino T, et al. JAK2V617F + myeloproliferative neoplasm clones evoke paracrine DNA damage to adjacent normal cells through secretion of lipocalin-2. Blood. 2014;124:2996–3006.
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015;100:479–488.
   PubMed Web of Science ®Google Scholar
• Barosi G, Zhang M-J, Peter Gale R. Does ruxolitinib improve survival of persons with MPN-associated myelofibrosis? Should it? Leukemia. 2014;28:2267–2270.
   PubMed Web of Science ®Google Scholar
• Mikkelsen SU, Kjær L, Skov V, et al. Safety and efficacy of combination therapy of interferon-α2 and ruxolitinib in polycythemia vera and myelofibrosis. Cancer Med. 2018;7(8):3571–3581.
   Google Scholar
• Bjørn ME, de Stricker K, Kjær L, et al. Combination therapy with interferon and JAK1-2 inhibitor is feasible: proof of concept with rapid reduction in JAK2V617F-allele burden in polycythemia vera. Leuk Res Rep. 2014;3:73–75.
   PubMedGoogle Scholar
• Bjørn ME, Hasselbalch HC. The role of reactive oxygen species in myelofibrosis and related neoplasms. Mediators Inflamm. 2015;2015;1–11.
   Web of Science ®Google Scholar
• Bjørn ME, Holmström MO, Hasselbalch HC. Ruxolitinib is manageable in patients with myelofibrosis and severe thrombocytopenia: a report on 12 Danish patients. Leuk Lymphoma. 2016;57:125–128.
   PubMed Web of Science ®Google Scholar
• Rasmussen ST, Andersen JT, Nielsen TK, et al. Simvastatin and oxidative stress in humans: a randomized, Double-blinded, Placebo-controlled clinical trial. Redox Biol. 2016;9:32–38.
   PubMed Web of Science ®Google Scholar
• Di Bona D, Cippitelli M, Fionda C, et al. Oxidative stress inhibits IFN-alpha-induced antiviral gene expression by blocking the JAK-STAT pathway. J Hepatol. 2006;45:271–279.
   PubMed Web of Science ®Google Scholar
• Wang JX, Gao J, Ding SL, et al. Oxidative modification of miR-184 enables it to target Bcl-xL and Bcl-w. Mol Cell. 2015;59:50–61.
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Gotlib J, Levy RS, et al. Long-term outcomes of ruxolitinib therapy in patients with myelofibrosis: 3-year update from COMFORT-I. Blood. 2013;122:396. http://bloodjournal.hematologylibrary.org/content/122/21/396.abstract
   Google Scholar
• Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013;122:4047–4053.
   PubMed Web of Science ®Google Scholar
• Parampalli Yajnanarayana S, Stübig T, Cornez I, et al. JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms. Br J Haematol. 2015;169:824–833.
   PubMed Web of Science ®Google Scholar
• Keohane C, Kordasti S, Seidl T, et al. JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells. Br J Haematol. 2015;171:60–73.
   PubMed Web of Science ®Google Scholar
• Schonberg K, Rudolph J, Vonnahme M, et al. JAK inhibition impairs NK cell function in myeloproliferative neoplasms. Cancer Res. 2015;75:2187–2199.
   PubMed Web of Science ®Google Scholar
• Sarvaria A, Basar R, Mehta RS, et al. IL-10+ regulatory B cells are enriched in cord blood and may protect against cGVHD after cord blood transplantation. Blood. 2016;128:1346–1361.
   PubMed Web of Science ®Google Scholar
• Lai Z, Hanczko R, Bonilla E, et al. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2012;64:2937–2946.
   PubMed Web of Science ®Google Scholar
• Shen Y, Cai W, Lei S, et al. Effect of high/low dose N-acetylcysteine on chronic obstructive pulmonary disease: a systematic review and meta-analysis. COPD. 2014;11:351–358.
   Google Scholar
• Conrad C, Lymp J, Thompson V, et al. Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial. J Cyst Fibros. 2015;14:219–227.
   PubMed Web of Science ®Google Scholar